Chrome compounds having SRS{13 A properties

ABSTRACT

There are provided compounds of the formula   WHEREIN X is a straight chain alkylene group containing from 3 to 7 carbon atoms and is unsubstituted or is substituted by one hydroxy group, E is a carboxy group AND R1, R2 and R3 may be the same or different and are hydrogen, hydroxy, methoxy, benzyloxy, acetyl, acetylamino, allyl or propyl AND R4 is hydrogen, allyl or propyl, AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF. The compounds are indicated for use as antagonists of SRS-A, the slow reacting substance of anaphylaxis.

United States Patent [1 1 Augstein et al.

[ May 6,1975

[ CHROME COMPOUNDS HAVING SRS-A PROPERTIES [75] Inventors: JoachimAugstein, Lindford; David Carter; Thomas Brian Lee, both ofLoughborough, all of England [73] Assignee: Fisons Limited [22] Filed:July 31, 1972 [21] Appl. No.: 276,798

[56] References Cited UNITED STATES PATENTS 7/1970 Fitzmaurice et al.260/3452 6/l972 Cairns et al 260/3452 Primary Examiner.lohn M. FordAttorney, Agent, or Firm-Wenderoth, Lind & Ponack [57] ABSTRACT Thereare provided compounds of the formula wherein X is a straight chainalkylene group containing from 3 to 7 carbon atoms and is unsubstitutedor is substituted by one hydroxy group, B is a carboxy group and R R andR may be the same or different and are hydrogen, hydroxy, methoxy,benzyloxy, acetyl, acetylamino, ally] or propyl and R is hydrogen, allylor propyl, and pharmaceutically acceptable salts thereof.

The compounds are indicated for use as antagonists of SRS-A, the slowreacting substance of anaphylaxis.

25 Claims, N0 Drawings CHROME COMPOUNDS HAVING SRS-A PROPERTIES Thisinvention relates to new compounds, methods III for their preparationand compositions containing 5 them.

According to our invention we provide compounds of formula or an esterthereof, I, in which R, R and E are as defined above, and

l0 Z is hydrogen or a reactive metal, or a hydrocarbon 7 chaincontaining from 2 to 10 carbon atoms and carrying an anion forming groupor an epoxide group, 1 I with a compound of formula IV, 0X0 R l5 3 2 R7R R YO R wherein R, R", R, R", R and R may be the same or differ- 3 l 2ent, and are hydrogen, hydroxy, alkoxy, alkoxy substi- R R tuted byphenyl, acyl, amino, acylamino, alkenyl, halogen, or alkyl, providedthat at least one of R, R R wherein R, R, R and R" are as defined above,and and R are other than hydrogen and hydroxy, Y represents hydrogen ora reactive metal when Z or an adjacent pair of R, R, R and R represent arepresents a hydrocarbon chain containing from 2 to chain COCl-l=CH-O,l0 carbon atoms carrying an anion forming group or an X is a hydrocarbonchain containing from 2 to [0 epoxide group, and, when Z representshydrogen or a carbon atoms and optionally substituted by a hydroxyreactive metal, Y represents a hydrocarbon chain congroup, and tainingfrom 2 to 10 carbon atoms and carrying an E is a carboxy group or atetrazole group, anion forming group or an epoxide group, andpharmaceutically acceptable derivatives thereof. c. producing a compoundof formula la by hydroly- According to our invention we also provide aprocess sing a compound of formula Xlll,

for the production of a compound of formula I, or a pharmaceuticallyacceptable derivative thereof, which 7 O 5 comprises, R R XIII a.producing a compound of fonnula la,

0x0 R 0 D R R Ia o u 3 2 R R R 0x0 R HOOC in which R, R, R, R", R R" andX are as defined q 2 above, and R R R D represents a group hydrolysableto a COOH group in which R, R R, R, R, R and X are as defined d.producing a compound of formula lb, above, by cyclising a compound offormula ll,

7 R l R R A 1 1 OX 2 R II wherein R, R, R, R, R, R and X are as definedabove, and in which R, R R, R, R, R and X are as defined A and A are thepairs of groups above, by reacting a compound of formula XIV, i. OH andCOCH COCOR, or 7 ii. OC(COOM)=CHCOOM and l-l R in which R is an OM groupor a group hydrolysal ble thereto, and R M is hydrogen or an alkalimetal, XIV b. reacting a compound of formula III, R R

in which R, R R, R, R R and X are as defined above,

with an azide in a solvent which is inert under the reaction conditions,

e. producing a compound of formula lo,

R R7 XVI COCH=C 2 0X0 E m @011 4 in which R, R R, X and E are as definedabove, and

L is an alkyl group, or

f. producing a compound of formula Id,

wm E i I oxo in which R, R, R", R, X, L and E are as defined above, byreacting a compound of formula XVII,

coca

R1 XVII in which R, R, R R, X and E are as defined above, with acompound of formula XVIII,

HCONL XVIII or an aceta] thereof,

in which L is as defined above,

and where desired or necessary converting the resulting compound offormula I to a pharmaceutically acceptable derivative thereof or viceversa.

The cyclisation of process (a) (i) may be carried out by heating, orunder basic or neutral conditions. It is however preferred to carry outthe cyclisation in the presence of an acid, e.g. hydrochloric acid, andin a solvent which is inert under the reaction conditions. The reactionmay be carried out at from about 20 to C. The group COR is preferably anester group in which, for example R is a lower alkanol group.

The cyclisation of process (a) (ii) may be carried out by treating thecompound of formula II with a cyclising agent, for example a dehydratingagent such as polyphosphoric, chlorosulphonic or sulphuric acid.

The reaction is preferably carried out under anhydrous conditions.Alternatively cyclisation may be achieved by converting the free carboxygroups of the compound of formula II to acyl halide groups andsubjecting the resulting acyl halide to an intramolecular Friedel-Craftsreaction.

Process (a) (i) is in particular useful when R, R R and R do not includean OH group and a COCH in adjacent positions. Process (a)(ii) is inparticular useful when R, R R and R do not include an OH group andhydrogen in adjacent positions.

In process (b) when Y or Z is a reactive metal the metal may be, forexample, an alkali metal, e.g. sodium or another reactive metal, e.g.thallium. When Y or Z represent a hydrocarbon chain carrying an anionforming group the anion forming group may be, for exam ple, a halogenatom, e.g. bromine, or a sulphonate group, e.g. a methyl sulphonate or ap-toluenesulphon ate group. When Y or Z represents a hydrocarbon chaincarrying a halogen atom the reaction may be carried out in the presenceof a solvent which is inert under the reaction conditions, e.g. acetoneand in the presence of an acid acceptor, e.g. potassium carbonate. Thereaction is also preferably carried out under anhydrous conditions andin the presence of a suitable catalyst, e.g. KI. When Y or Z represent ahydrocarbon group carrying an epoxide the reaction may be carried out atan elevated temperature in a solvent which is inert under the reactionconditions, e.g. dioxan or dimethylformamide, and in the presence of asuitable catalyst, e.g. trimethylbenzylammonium hydroxide.

In process (c) the group D may be, for example, an ester, amide ornitrile group, which may be hydrolysed to a COOH group. The hydrolysismay be carried out using conventional techniques, for example, undermildly basic conditions, e.g. using sodium bicarbonate.

Suitable solvents which are inert under the reaction conditions ofprocess (d) include those in which both the reagents are soluble, e.g.N,N-dimethylformamide. Other solvents which may be mentioned includedimethylsulphoxide, tetrahydrofuran, diethyl glycol and ethyl methylglycol. The reaction is preferably carried out at a temperature of fromabout 20 to I30C for from about 1 to 20 hours. The azide used in thereaction is preferably ammonium or an alkali metal azide, e.g. sodium orlithium azide, but other azides, e.g. aluminium azide or the azides ofnitrogen containing bases, e.g. monoditriand tetramethylammonium,anilinium, morpholinium and piperidinium azides, may also be used ifdesired. Where an azide other than that of an alkali metal is used thisazide may be prepared in the reaction mixture by double decomposition.The reaction may, if desired, be carried out in the presence of anelectron acceptor, e.g. aluminium chloride, boron trifluoride, ethylsulphonic acid or benzene sulphonic acid. As an alternative to thereaction conditions set out above the reaction may be carried out usinghydrazoic acid (hydrogen azide) at a temperature of from about 20 to150C in a suitable solvent, under greater than atmospheric pressure.When an azide other than hydrazoic acid is used, e.g. sodium azide, theproduct of the reaction will be the corresponding tetrazole salt. Thissalt may readily be converted to the free acid by treatment with strongacid, e.g. hydrochloric acid. Process (d) is believed to pass through acompound of formula XV,

in which R, R R, R, R R and X are as defined above. The cyclisation ofprocess (e) may be carried out under the same conditions as process(a)(i).

In process (f) it is preferable to use an acetal of the compound offormula XVII], for example a di-alkyl acetal, e.g. a dimethyl acetal.The reaction may conveniently be carried out at an elevated temperature,e.g. from about l00 to 200C, in a solvent which is inert under thereaction conditions, e.g. xylene.

Compounds of formula ll may be made by reacting a compound of formula V,

OZ V

in which A, A R", R and Z are as defined above, with a compound offormula V],

in which R, R R, R and Y are as defined above, under the conditions ofprocess (b).

Compounds of formula ll in which A and A are the pair of groups OH andCOCH COCOR, and in particular those compounds in which an adjacent pairof R, R, R and R are not an OH group and a COCH group, may also be madeby reacting a compound of formula Vll,

in which R, R, R, R, R R and X are as defined above,

with a dialkyl oxalate, e.g. diethyl oxalate in manner known per se.

Compounds of formula ll in which A and A are the pair of groupsOC(COOM)=CHCOOM and H and in particular those compounds in which anadjacent pair of R, R, R and R are not an OH group and hydrogen, may bemade by reacting a compound of formula Vlll,

OX0 R VIII HO R R R in which R, R, R, R, R, R and X are as definedabove, with acetylene dicarboxylic acid or an ester thereof in mannerknown per se.

Compounds of formula Vll and VII] may be made by linking a compound offormula 1x or X,

CH CO H OZ OZ X HO HO IX R R respectively, with a compound of formulaX1,

in which formulae R, R R R, R", R", Z and Y are as defined above, usingthe same techniques as in process (b) above.

Compounds of formula XIV may be made by dehydrating the corresponding2-carboxyamide using, for example, phosphorous oxychloride, asdehydrating agent. The reaction is preferably carried out using at leastone molar equivalent of dehydrating agent per mole of carboxyamide.Where the dehydrating agent reacts with one of R, R, R", R, R R or X(e.g. a substituent comprising an OH group) sufficient dehydrating agentshould be used to satisfy the side reaction as well as the mainreaction. The reaction may, if desired, be carried out in the presenceof an acid binding agent, e.g. triethylamine. The reaction may becarried out in the presence of a solvent, e.g. N,N-dimethylformamide,dimethyl sulphoxide, pyridine, benzene or hexamethyl phosphoramide, oran excess of the dehydrating agent may be used as the reaction medium.The reaction may be carried out at a temperature of from about 0 to 200Cdepending on the dehydrating agent used. When phosphorus oxychloride isused a temperature of from 0 to C is preferred.

The 2-carboxyamides may be made in manner known per se by reacting thecorresponding 2-carboxylic acid esters with ammonia, e.g. using analkanol as a solvent at a temperature of to 120C.

The compounds of formulae V, VI, XI, X and XVII] are either known or maybe made from known starting materials in a manner known for theproduction of similar known compounds. Compounds of formula XVI may bemade by process (f) above and compounds of formula XVII may be made byany one of processes (a), (b) or (c) above.

The compounds of formula I, and where desired or necessary, theintermediates therefor, may be recovered from the reaction mixtures inwhich they are produced by conventional techniques.

Those of the compounds of formula I in which E is a carboxy group and anadjacent pair of R, R R and R are (a) an OH group and hydrogen, or (b)an Ol-l group and a COCI-l group, are useful as intermediates in theproduction, by methods analogous to process (a) above, of a compound offormula XII,

XII

HOOC COOH in which R, R and X are as defined above and R and R are theremaining groups of R R R and R as defined above. The compounds offormula Xll are themselves, or in the form of their sodium salts, usefulat a dosage of l to 50 mgs. in the relief or prevention of allergicairway obstruction, tag. the treatment of allergic asthma.

The compounds of formula I and their pharmaceuti cally acceptablederivatives, for example their pharmaceutically acceptable salts, estersand amides, e.g. their sodium, lower alkylamine, e.g. ethylamine, andhydroxy substituted lower alkylamine, salts, are also useful becausethey possess pharmacological properties. In particular the compounds areantagonists of the slowreacting substance of anaphylaxis (SRS-A), or itspathological effects, as is indicated by their activity in the test setout in Example A. The compounds also antagonise the effects of SRS-Aobtained during antigen challenge of sensitized human chopped lung onisolated guinea pig ileum as described in Example A. The compounds alsohave the same utility at the same dosages as the compounds of Dutch Pat.Specification No. 6,81 l,740.

The compounds are thus useful in the treatment of disorders in whichSRS-A is a factor, for example skin afflictions, hay fever andobstructive airways diseases, e.g. asthma.

For the above-mentioned uses, the dosage administered will, of course,vary depending upon the compound employed, mode of administration andtreatment desired. However, in general satisfactory results are obtainedwhen administered at a daily dosage of from about I milligram to about10 milligrams per kilogram of animal body weight, preferably given individed doses 2 to 4 times a day or in sustained release form. For thelarger mammals, the total daily dosage is in the range of from about 50milligrams to about 700 milligrams, and dosage forms suitable foradministration comprise from about l2 milligrams to about 350 milligramsof the compound admixed with a solid or liquid pharmaceutical carrier ordiluent. The compounds may be administered during or before the attackof the disorder to be treated.

The compounds may be administered in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier, the composition used dependingon many factors including the disorder to be treated. The compounds maybe administered parenterally by inhalation or topically.

The invention also provides a process for the produc tion of apharmaceutically acceptable salt of a compound of formula I, whichprocess comprises treating a compound of formula I, an ester or amidethereof or another salt thereof with an appropriate base, e.g. a sodiumbase or with an appropriate salt by a metathetical process.

As a specific group we provide those compounds of formula I in which Eis a carboxy group and an adjacent pair of R R, R and R" are not (a) anOH group and hydrogen, or (b) an OH group and a -COCl-l group. Thosecompounds in which the OXO group is attached to the chromone group inthe 7 position are preferred as are those compounds in which E is atetrazole group.

It is preferred that R is hydrogen and R is hydrogen, lower alkyl orlower alkenyl. It is also preferred that R should be in the 6 or 8position.

It is preferred that no more than 3 of R, R R and R are other thanhydrogen. Preferred values of R, R R, R, R and R are hydrogen, hydroxy,lower alkoxy, lower alkoxy substituted by phenyl, lower acyl (e.g. loweralkanoyl, lower alkenoyl, or lower alkenoyl substituted by an amino or amonoor di-loweralkyl amino group), amino, lower acyl amino (e.g. loweralkanoylamino), lower alkenyl, halogen (e.g. chlorine, bromine oriodine) or lower alkyl.

Specific examples of values of R, R R, R, R and R are hydrogen, hydroxy,methoxy, benzyloxy, acetyl, dimethylaminoacryloyl, amino, acetylamino,allyl, methyl, ethyl, propyl and butyl.

Preferred compounds of formula I are those in which R is hydrogen, R ishydrogen, propyl or allyl, R" is hydrogen, R is hydrogen, propyl orallyl, R is hydroxy and R is acetyl.

The group X is preferably a straight chain alkylene group containing,for example, from 3 to 7 carbon atoms and optionally substituted by ahydroxy group.

In this specification and in the claims lower is used to mean a groupcontaining up to and including 6 carbon atoms.

The invention is illustrated, but in no way limited by the followingExamples, in which temperatures are in C.

EXAMPLE l 7-[ 5-( 4-Acetyl-3-hydroxyphenoxy )pentyloxy]-4-oxo- 4H- 1-benzopyrancarboxylic acid a. 4-(5-Bromopentyloxy)-2-hydroxyacetophenoneTo a mixture of 34 parts of 1,5-dibromopentane, 9.2 parts of potassiumcarbonate and 0.5 parts of potassium iodide, in parts of dry acetone,was added, dropwise with stirring, a solution of 20 parts ofresacetophenone in 200 parts of dry acetone and the mixture heated underreflux for 18 hours.

The mixture was filtered while hot and the inorganic salts washed withhot acetone. The acetone solution was evaporated to leave an oil whichwas triturated with 200 parts of diethyl ether. The insoluble solid wasTo a solution of 2.0 parts of ethyl 7-[5-(4-acetyl-3-hydroxyphenoxy)-pentyloxy]-4-oxo-4H-l-benzopyran- Z-carboxylate in lparts of ethyl alcohol was added 2.0 parts of sodium bicarbonate and themixture boiled filtered and the ethereal solution extracted with 2%% 5 nthe steam can for 2 hours. During this period water Sodium hydroxide8010mm, washed with water, dried was added and the ethyl alcohol allowedto evaporate. over magnesium sulphate, filtered and the solvent r Theaqueous solution was filtered and acidified with moved to leave an oilwhich solidified on standing. The dil t hyd hlori acid to give a whitesolid, which solid was recrystallised from [MS to yield p of wasfiltered and crystallised from ethyl alcohol and di- P Y Y)- y y p asoxan to yield 1.6 parts of 7-[5-(4-acetyl-3- lourless needles, meltingpoint 63.565C. hydroxyphenoxy)pentyloxy1-4-oxo-4H-l-benz0pyran-Z-carboxylic acid as off white needles, melting point 226-228C.Analysis:

Found: C, 52.2; H, 5.8l%. C H BrO requires: C, SL831 H, 5.65%.

Analysis:

Found: C, 64.4; H, 5.34. b E h C H O requires: C, 64.78; H, 5.20.7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-4-oxod 4H- l-benzopyran2-carboxylatc 7-[5-( 4-Acetyl-3-hydroxyphenoxy)pentyloxy1-4-oxo- A mixture of 305 parts of 4 (5 br0mopemyloxy) 24H-l-benzopyran-2-carboxylic acid sodlum salt hydroxy acetophenone, 2.34parts of ethyl 7-hydroxy A mixture of 3.35 parts of 7-[5-(4-acetyl-3-4-oxo-4l-l-l-benzopyran-Z-carboxylate, 1.38 parts of hydroxyphenoxypentyloxy]-4-oxo-4H-l-benzopyrant ium arb nat and 05 parts f potassium idid 2-carboxylic acid and 0.66 parts of sodium bicarbonate in 200 partsof dry acetone, was heated under reflux for 200 Parts Of was heated toeffect luti n- The 24 hours. The solution was filtered while hot and thewas filtered While hot and Cooling a whim inorganic salts washed withhot acetone. The solvent sohd crystanlsed- Thls was filtered, washedwith was removed to leave a yellow solid, which was washed cold and qunder Vacuum Phosphorus with water and ether. The insoluble yellow solidwas fi g h to weld Parts of crystallised from ethyl alcohol to yield 3.3parts of ethyl mbxyp lf zf g f i z fogg v"7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy1-4-oxot so mm Sa me pomt4H-l-benzopyran-Z-carboxylate as pale yellow needles, e melting pointl36-l37C.

Analysis:

Found: C, 60.7; H, 4.57. Analysis: CuH2]NaOBVH2O requires: C, 60.4; H,.8l.

Found: C, 66.05; H, 5.74. CaHggOg requires: C, 66.05; H, 5.77. EXAMPLE 2c. 40 Using the same process as in Example I, but substi-7-[5-(4-Acetyl-3-hydroxyphenoxy)pentyloxy]4-oxotuting appropriatestarting materials, the compounds 4H-l-carboxylic acid (and their sodiumsalts) shown in Table l were made.

mm; I

corrmo nd Analvsis no C Analysis of wziiun salt i-Ai1,-1-7-5-(u-aeecl-z-all l-a-h drm i Found! c, 58.9 a, 6.08

caoxy pentyloxy7 4-oxo-QH-l-benzopymn C H O Requires: C, 68.76 H, 5.57196-7 :a:lx xylic acid 29 3O 8 i L'l-7L'T ;-acetylphenoxyfipentyloxy]Found: C, 69.60 5.9M Found: C, 65."? zaliz-l-Ennzopyran-Q-carboxyhc acidC i1 0 REGLLLIQS: C, 69.37. .a 5. 2 201-3 C Ei .laJ .;ii O l'cquires: C65.1. h, 5&3

8-!u.1 'l.7-[5(2-acetyl- Found: C, 57. H, 5.87 ihrdoxypiienmg)pentyloxfl- -oxo-QH- C., H O Requires: C, 67.0 ll, 5.62 171-I. groan-Z-ccrrboxylic acid 5 25 8 B-!t lyl-7[5-( +-acetyl aminopnenoxy) Found: C, 65.65 1!, 5.75 penfiy'Lox jl-oxotli-lbenzopyrian-2-35, 2.8 4 U Found: (3, 61.8 i1, i 3.62 carxnglic acld C ri NO Ql-Z ORequlresz C, 65.7 2.2; 126-8 C2BH2sNllG07'fi2O Fequn'cs: L, 51.8 H, a 54i .77

tylpiicnoxflpentyloxy] Found: C 67.15 H, 5N2 -benzop' rzanfl-carboxylicC23H22O7 Requires: C, 67.) 15, 5. 40 219-221 -Icthoxyhenoxyknntyloxfl-U- Found: C, SEEMS ii, 5.57 V 61.7 i, :MZkl-cenzony'nan-Z-carboxyhc acid C rl O Requires: C, 66.32 ii, 5.57 -7 Cri .1a3 ol.5 it, a....

IT, ".52 5.23 l'. e :1. ei-3 CZSKZESYDT F213 5 25 Po (1: c 66.9k H, 5.62

EXAMPLE 3 8-Allyl-7-[ 3-( 4-acetyl-2-allyl-3-hydroxyphenoxy 2-hydroxypropoxy ]-4-oxo-4H- l -benzopyran-2- carboxylic acid a.3-Allyl-4-( 2,3-epoxypropoxy )-2-hydroxyacetophenone To a solution of19.2 parts of 3-allyl-2,4- dihydroxyacetophenone and 24.0 parts ofl-chloro-2,3-epoxypropane in l parts of ethyl alcohol, heated underreflux, was added a solution of 6.6 parts of potassium hydroxide in 3.0parts of water and 25.0 parts of ethyl alcohol, dropwise with stirring,and the mixture stirred and heated under reflux for 2 hours.

Water and ether were added, the ether layer was separated, dried overmagnesium sulphate, filtered and the solvent removed to leave a yellowoil. The oil was distilled at reduced pressure to yield 16.] parts of3-allyl- 4(2,3-epoxypropoxy)-2-hydroxyacetophenone as a white solid,melting point 6667.5C.

Analysis: Found: HI-1, 0. requires:

b. Ethyl 8-allyl-7-hydroxy-4-oxo4l-ll -benzopyran-2- carboxylate To astirred solution of sodium ethoxide in ethyl alcohol, prepared from 2.3parts of sodium and 50.0 parts of ethyl alcohol, was added a slurry of4.8 parts of 3- allyl-2,4-dihydroxyacetophenone and 9.15 parts ofdiethyl oxalate in 50.0 parts of diethyl ether. The mixture was stirredand heated under reflux for 4 hours.

Water and diethyl ether were added and the aqueous layer was separated,acidified with dilute hydrochloric acid, and extracted with ethylacetate. The organic layer was separated, dried over magnesium sulphateand the solvent removed to leave a red oil. The oil was dissolved inethyl alcohol and 0.5 parts of concentrated hydrochloric acid were addedand the mixture heated under reflux for l5 minutes. The solvent wasremoved to leave an oil which was dissolved in ethyl acetate and washedwith sodium bicarbonate solution. The organic layer was separated andevaporated to a yellow solid which was crystallised from diethyl etherto yield 3.6 parts of ethyl 8-allyl-7-hydroxy-4-oxo-4H-lbenzopyran-Z-carboxylate as a pale yellow solid, melting point l64l65C.

Analysis:

Found. C, 65.1; C H OI. requires: C, 65

c. 8-Allyl-7-[ 3-(4-acetyl-2-allyl-3-hydroxyphenoxy)-2- hydroxypropoxyl-4-oxo-4H-l -benzopyran-2- carboxylic acid 5 To a solution of 5.5 partsof thyl 8-allyl-7-hydroxy- 4-oxo-4H-l-benzopyran-2-carboxylate and 5.0parts of 4-(2,3-epoxypropoxy)-3-allyl-2-hydroxyacetophenone in 50 partsof dimethylformamide was added 0.5 parts of benzyltrimethyl ammoniumhydroxide and the mixture heated under reflux for 4 hours.

The solvent was removed to leave a brown oil, which was dissolved inethyl acetate and extracted with 0.5N sodium hydroxide, dried overmagnesium sulphate, filtered, and evaporated to dryness.

The oil remaining was dissolved in ethanol and by drolysed by boilingwith an aqueous solution of sodium bicarbonate. The solution wasextracted with ether and the aqueous layer separated and acidified withdilute hydrochloric acid. The precipitated solid was filtered and addedto 50 parts of saturated sodium bicarbonate solution to give aprecipitate of the insoluble sodium salt. The solid was filtered, washedwith parts of cold water and the resultant white solid dissolved in hotwater and acidified with dilute hydrochloric acid to yield 3.0 parts of8-allyl-7-[3-(4-acetyl-2-allyl-3- hydroxyphenoxy )-2-hydroxypropoxy-4-oxo-4H- l benzopyran-Z-carboxylic acid, crystallised from benzene asa pale yellow solid, melting point 105C(indefiallyl-3-hydroxyphenoxy)-2-hydroxypropoxy]-4-oxo-4H-l-benzopyran-2-carboxylic acid and 0.584 parts of sodium bicarbonatein 500 parts of water was freeze dried to yield 3.5 parts of8-allyl-7-[3-(4-acetyl-2-allyl- 3-hydroxyphenoxy )-2-hydroxypropoxy4-oxo-4H- l benzopyran-2-carboxylic acid sodium salt as a white solid,melting point 249-25 1C.

Analysis:

Found: C,

4.90, C H Nao requires: C, 4.88.

EXAMPLE 4 Using the same process as in Example 3, but substitutingappropriate starting materials, the compounds (and their sodium salts)shown in Table ll were made.

mm: II

m y min-i EM Q-Ul-Acetyl-il-hydzoxyphemxfl-Z- Found: C, 60.0 H, .28

mxypmpoxyJ-H-oxo-HH-l-benmpymn C l-l .H O Requires: C, 59.5 H, J49 251-2e mboxylic acid Bgrallylygfihxo-aeetyl-iiziydmxy- Fcund: c, 61.8 H, 5.12rm; c, 55.5 H, m2 pemxy xypropo '-l-0xo'+H C 0 0 Re uires: C 52.2 HI$.97 205 C H N50 0 Re ui'ms: C 58.3 H ".61 l-benzopymn-Z-carlinxylicacid H22 9 2 q n 9 H2 q 7-[3-(i-Acetyl-B-hydmxyJ-allyl- FOu'nd: c, 59.8H, .95 piunoxyl-Z-hydroxypropoxyl-t-om C H JH O Requires: C, 59.9 H,5.19 120-5 lli-l-renzopyrmnfl-carboxylic acid E-Pm;yl7-Z3;(l-:1cetyl-3-hy1%xy2- Found: C, 6M7 H, 6.22 Found: C, 59AM H, 5.7% prop;pnenoxy -2-iydmxypmpo 4-0): 0 i 0 uires: C 65.0H 6.1.1 206-7 0 N30 .1 0mixes: C 59.23 H 5.85 r;i-l-benzopyran-2carboxylic acid 27] 30 g Esq2714129 9 H1 Req i-0xo-8-propy1-7-[3(Z-pmpylphenoxy) Found: C, 67.87 H,6.48

h;rdmxypmpoxy]- ll-l-l-benzopymn C25H2807 Requires: C, 68.17 H, 6. m].129-130 -i-carbaxylic acid A-Jx/J-l-El-(2-pmpylphenoxyJ-2- Found: C,56.62 H, 5.56 hydzvmypmpoxyY-HH-l-taenzcpyran-2- (322B 0 Requires: C,66.32 H, 5.57 ri l-175 cerboxylic acid 27-[3-(2-A11vlphsnoxy)2-hyrlmxypmpoxy] Found: C, 56.38 H, 5.2 -u-o;w#lll-bonzopyran-2-carboxylic acid CHHZOO7 Requires: 0, 55.56 H, 5.0!181-183 7[3-(H-Acetyl3-hydroxy2- propllnhemxyJ-Z-hydroXyptQpoYy] Found:C, 61.89 B, 5.10 -oxo-Hll-l-benzopynan-Z- C H 0 .}l-l 0 Requires: C,61.90 H, 5.37 190-195 car oxylic acid hemihydnate 7- ('4Acetyl-3-hydmxy2-propylphenoxy) -?hvdmxvpmpoxy]-H-oxo-6-pmpyl-HH1-benzap'nan-2-car'l'nxylic acid Found: C, $4.93; H, 6.08

c n o Requires: c, 65.06, H, 6.02 205 u zgg aql fq d: C 5L0 H, SJ;Found: C, 61.9 H, 6.0 fii 3 s 68- H. a. 215-216 H NaD lH 0 Requues: c,at. a, 6.1

7-52: 'jrgxy-ii-sgflll-geinethylphenoxyl Found: C, 65. H, 5.3 Found: C,56.2 H, 5." nzopynan-Z- G i-{ 0 Requnes: C, 65.6 H, 5.2 179-181C21H19M07.2H20 Requires: C, 56.1 Ii, 5.3

Z-itfl,H-Di-t-hxtylphfmflJ-Z- Found: c, 69.6 a, 1.0 Fqllnd: c, 52.6 H,6.6 gfig fgfig fig i (2 5 0 Reqlnx'es: c, 69.2 H, 6.9 227-228 c l1 1iao.1ia o Requires: c, 52.7 H, 6.2

g-riaJz-t-aur t enex z zi Found: c, 63.9 H, 6.1 3/ Found: c, so.u H, 5.7t hfz m za boiy ic acid za zu r'h Regimes Ci zs n r' 2" Reqms EXAMPLE 5A mixture of 4.6 parts of 7-(5-bromopentyloxy)4- 7 [5 (4 oxo 4H lbenzopyran 7 yloxy)pemyloxy]4 oxo-4H-l-benzopyran-2-carboxyl1c acid,ethyl ester, 2 0Xo 4H 1 benZ0pymn 2 carboxylic acid 40 parts of ethyl7-hydroxychromone-2-carboxylate, l.8 parts of potasslm carbonate, a fewpotassium iodide crystals and 80 parts by volume of dry acetone was refj fluxed on a steam bath for 20 hr. The cooled mixture carboxyhc acid;ethyl ester was filtered and the filtrate evaporated down to give an 20parts of 7-hydroxy.4-oxo 4H benz0pyran 2 when treated petroleum ether(40 -60 carboxylic acid ethyl ester were stirred and refluxed solldlfied8 Part5 Ofcrude Product crystallisawith 40 parts dibromopentane and 12parts potassium hon from ethanol g 29 parts of carbonate in 600 parts byvolume of dry acetone. The nz pyran-7-y y)p ty ylmixture was refluxedfor 18 hr., cooled and filtered. Py I- Y acld; ethyl ester, -p- Theacetone filtrate was evaporated to dryness to give an oil. Petroleumether (40-60) was added and after some time the oil slowly solidified togive a sticky solid. This crude product was purified by dissolving it inbenzene and slowly adding petroleum ether (4060). A I

na ySlSZ 10.2 parts of 7-(s-brornopentyloxy)-4-oxo-4l-I-l- Found: C, 6;H' 5,16% benzopyran-Zcarboxylic acid; ethyl ester separated C,,H,,0,reuires; Q6713; H. 5.21%. out as a white solid, mp. 72-8, raised to 78-79,(from petroleum ether -80).

0 C. I 7-[ 5-( 4-Oxo-4H- l -benzopyran-7-yloxy )pentyloxy]4- Ana ysis:

Found; C, 535; H 499%. 0x0 41-! l benzopyran 2 carboxyhc acid 533; 496%A mixture of 5 parts of the ethyl ester from (b), 5 parts of sodiumbicarbonate, 70 parts by volume of water and 20 parts by volume ofethanol was warmed b. 7-[5-(4-oxo-4H-1-benzopyran-7-yloxy)pentyloxy]4-oxo-4H-l-benzopyran 2-carboxylic acid, ethyl ester and stirred on asteam bath for 30 min. The cooled aqueous solution on acidification gave4.6 parts of the required acid, m.p. 228-232C.

Analysis: Analysis:

Found: C, 65.8, H, 4.7%. Found: C, 61.7; H, 3.8%. C H O requires: C.66.05; H, 4.62%. C H O, requires: C, 62.28; H, 3.8%.

d. '-[5-(4-Oxo-4H-1-benzopyran-7-yloxy)pentyloxy14- xo-4H-l-benzopyran2-carboxylic acid; sodium salt 0.69 of a part of sodium bicarbonate wasadded in iall portions to 3.9 parts of the acid in 100 parts by lume ofwater. The solution was gently heated until arly all the acid was insolution. The neutral solution is filtered and freeze dried to give 3.6parts of the soum salt.

EXAMPLE 6 7-[3-(4-Oxo-4H-l-benzopyran-7-yloxy)-2'droxypropoxyl4-oxo-4H-l-benzopyran-2-carboxylic acid a. 7-(2,3-Epoxypropoxy )4-oxo-4H- l -benzopyran-2- carboxylic acid; ethylester A mixture of parts 7-hydroxy-4-oxo-4H-l nzopyran-Z-carboxylicacid; ethyl ester, parts epiomohydrin, 6 parts potassium carbonate and150 rts by volume of dry acetone was stirred and refluxed l8 hr. Thecooled mixture was filtered and the fil- .te evaporated down to give anoil, which solidified. is crude product was dissolved in ethyl acetatewhich s washed with sodium carbonate solution. The dried iyl acetateextract on evaporation gave 7 parts of the iyl ester, m.p. 124l27".Crystallisation from etha- I gave 6.3 parts of pure ethyl ester, m.p.l26l 28.

Analysis:

Found: C, 62.2; C H O. requires: C, 62.06;

b. 7-[ 3-(4-Oxo-4H- l -benzopyran-7-yloxy )-2- hydroxypropoxy]-4-oxo-4H-l -benzopyran2- carboxylic acid mixture of 7.16 parts7-(2,3-epoxypropoxy)-4- i-4H-l-benzopyran-2-carboxylic acid; ethylester, 4 ts ethyl 7-hydroxychromone-2-carboxylate, 12 p5 of Triton B,and 80 parts by volume of dimethyl mamide, was stirred and refluxed for6 hrs. The di thylformamide, was evaporated off and the residualextracted well with ethyl acetate leaving a sticky d. The ethyl acetateextracts were washed with som carbonate, dried and evaporated to givethe crude yl ester of the required acid. Crystallisation of this d fromethanol gave 0.69 of a part of this ester m.p. 1-6.

. mixture of 0.5 of a part of this ester, 0.l ofa part odiumbicarbonate, 8 parts by volume of water and arts by volume of ethanolwas warmed on a steam n for 2% hr. The filtered solution onacidification e 0.4 of a part of the required crude acid, m.p. 225.Crystallisation from ethanol gave 0.36 of a t of the required acid, m.p.243247.

c. 7-[ 3-( 4-Oxo-4H-l -benzopyran-7-yloxy )-2- hydroxypropoxy1-4oxo-4H-l -benzopyran-2-carboxylic acid; sodium salt 0.039 of a part of sodiumbicarbonate was added to 0.198 ofa part of the above acid in 12 parts byvolume of water. The solution was gently heated until it became neutral.The cooled solution was filtered and freeze-dried to give 0.2 of a partof the sodium salt.

EXAMPLE 7 7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxyl-4-oxo-8-propyl 4H-l-benzopyran-2- carboxylic acid tris(hydroxymethyl) methylamine salt monohydrate A solution of0. l 2l partsof tris (hydroxymethyl) methylamine in 25 parts of ethyl alcohol wasadded to a solution of 0.498 parts of 7-[3-(4-acetyl3-hydroxy-2propylphenoxy)-2-hydroxypropoxyl-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylic acid in 25 parts of ethyl alcohol and themixture heated on the steam bath for 5 minutes.

The solvent was removed under reduced pressure and 50 parts water added.The solution was filtered and freeze dried to yield 0.6 parts of7-[3-(4-acetyl-3- hydroxy-Z-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-l-benzopyran 2-carboxylic acid tris(hydroxymethyl)methylamine salt, monohydrate.

Analysis:

Found: C, 58.49; H, 6.64; N, 2.18. C ,H ,NO .H,O requires: C, 58.3]; H,6.74; N, 2.]9.

EXAMPLE 8 7-[ 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy1-4-oxo8-propyl-4H-1-benzopyran-2-carboxylic acid a. 4-(3-Bromopropoxy)-2-hydroxy-3- propylacetophenone A solution of 7.2 partsof sodium hydroxide in 100 parts of water was added slowly over one hourto a stirred, refluxing mixture of 144 parts of 1,3- dibromopropane, 35parts of 2,4-dihydroxy-3- propylacetophenone, and 300 parts of water.The mixture was heated for 5 hours and then stirred at room temperatureovernight. The organic phase was separated, and the aqueous phase wasextracted with chloreform. The organic layers were combined andevaporated to an oil which was distilled to give a fraction boiling at3236/0.02 mm., which was mostly l,3- dibromopropane, and a fractionboiling at l72-l /0.02 mm., which consisted of 23.5 parts of 4-(3-bromoprop0xy)-2-hydroxy-3- propylacetophenone.

7-[ 3-( 4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid A mixture of 16 partsof ethyl 7-hydroxy-4-oxo8- propyl-4H-l-benzopyran-2-carboxylate, 23.5parts of 4-( 3-bromopropoxy)-2-hydroxy-3 propylacetophenone, 10.7 partsof anhydrous potassium carbonate, 0.5 parts of potassium iodide, and 300parts of dry acetone was refluxed for 18 hours, and the hot solution wasfiltered. The residue was washed with hot acetone, and the combinedfiltrates were evaporated to an oil. The oil was dissolved in chloroformand washed with 1% sodium hydroxide solution, and water, dried andevaporated to an oil, which was hydrolysed by boiling with an aqueousethanolic solution of 5.5

parts of sodium bicarbonate over 1 hour. The reaction mixture wasdiluted with about 8000 parts of warm water and washed with ethylacetate. Acidification of the aqueous layer gave a solid, which wastaken up in 500 parts of hot ethanol, and to this was added a diluteaqueous solution of sodium bicarbonate. The mixture was allowed to coolwith the addition of small portions of ethanol to prevent gel formation.A gelatinous precipate of the sodium salt was obtained which wasfiltered off and washed with water. The precipitate was suspended inwater and acidified to give a solid, which was recrystallised from ethylacetate to afford 6.6 parts 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy1-4-oxo-8-propyl-4l-l-l-benzopyran-2-carboxylic acid, m.p. 173-174.

Analysis:

Found: C, 67 C H O requires: C, 67.20,

c. Sodium 7-[ 3-(4-acetyl-3-hydroxy---propylphenoxy)propoxyl-4-oxo-8-propyl-4H-1- benzopyran-Z-carboxylate To5.0 parts of 7-[3-(4-acetyl-3-hydroxy-2-propyl phenoxy )propoxyl-4-oxo-8-propyl-4H- l -benzopyran-2- carboxylic acid dissolved in 200parts of hot ethanol was added a solution of 0.870 parts of sodiumbicarbonate in 30 parts of water. The solution was evaporated underreduced pressure to dryness, dry benzene was added and the mixture wasagain evaporated to dryness. The resulting buff solid was ground to apowder and dried to afford 5.0 parts of sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-4-oxo-8- propyl-4l-ll-benzopyran-Z-carboxylate.

EXAMPLE 9 The compounds shown below were made using the techniquesdescribed in Example 8 and appropriate starting materials.

and

EXAMPLE l0 8-( 3-[ 2-t-Butylphenoxy]-2-hydroxypropoxy )-4oxo- 4H-l-benzopyran-2-carboxylic acid a. 3-( 2-t-Butylphenoxy)-l ,2-epoxypropaneTo a solution of 40 parts of o-t-butylphenol, parts of epichlorhydrin,and 40 parts of ethanol boiling under reflux with stirring was addeddropwise over 10 minutes a solution of 17.6 parts of potassium hydroxidedissolved in 66 parts of ethanol and the minimum amount of water. Themixture was stirred and refluxed for minutes, cooled, diluted withwater, and well extracted with ether, which was then washed with water,dried over magnesium sulphate, and evaporated to an oil. Distillation atl44l8 mm afforded 43 parts of 3-(2-tbutylphenoxy)-1,2-epoxypropane as aclear oil.

Analysis:

Found: C. 75.5; H, 8.9. C H O, requires: C, 75.7; H, 8.8%.

b. 8-( 3-[Z-t-Butylphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid A mixture of 16.7 parts of ethyl8-hydroxy-4-oxo-4H- l-benzopyran-2-carboxylate, 14.7 parts of3-(2-tbutylphenoxy)-l ,2-epoxypropane, 50 parts of dimethyl formamide,and 0.1 parts of benzyltrimethyl ammonium hydroxide was boiled underreflux for 3 hours, evaporated to leave a dark brown oil, and treatedwith ethyl acetate, which was then washed with 2% sodium hydroxidesolution, and water, dried, and evaporated to an oil. The oil waschromatographed on a silica column with chloroform as eluent to give agummy solid, which was boiled with an aqueous ethanolic solution ofsodium bicarbonate. The mixture was acidified to give a solid, which wasrecrystallised from ethanol after treatment with charcoal to give 4.6parts of 8-(3-[2-tbutylphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid as a cream solid, mp. 227-228 (decomp.).

Analysis:

Found: C, C l-l,,O .zH,O requires: C,

c. Sodium 8-( 3-[ 2-t-butylphenoxy]-2-hydroxypropoxy )-4-oxo-4l-l-l-benzopyran2-carboxylate sesquihydrate mg. C Analysis of sodiumsalt 5 Foimd: C, 67 5 8.3 55 152-163 C H IlaO Requires: C, 67.2 h, 6.05

6 Found: 0, 56.55 a, 6.1 65 138-139 C ll IlaO .l-l O Requires: C, 66.1H, 6.2

Analysis:

Found: C, C H NaO J/2H O requires: C.

EXAMPLE ll The compounds shown below were made using the techniquesdescribed in Example and the appropriate starting materials.

of sodium bicarbonate and l50 parts of ethanol were boiled while waterwas slowly added to make up the volume as the ethanol was removed. Whenhydrolysis was complete the part aqueous solution was washed 5 withether, cooled and acidified to afford a cream solid. Crystallisationfrom aqueous ethanol afforded 8.2 parts of 8-[3-(2-n-butylphenoxy)propoxyl-4-oxo-4H-lbenzopyran-2-carboxylic acid mp l68l68.5C.

Analysis:

Found: C. 69.6; H, 6.2. C H O, requires: C. 69.7; H, 6.1%.

c. Sodium 8-[3-( Z-n-butylphenoxy )propoxy ]-4-oxo-4H- lbenzopyran-Z-carboxylate monohydrate A mixture of 8.0 parts of8-[3-(2-nbutylphenoxy )propoxy ]-4-oxo-4H-l -benzopyran-2- carloxylicacid EXAMPLE l2 8 3-[ 2-n-butylphenoxy lpropoxy )-4-oxo-4H-lbenzopyran-Z-carboxylic acid a. 3-Bromopropyl-2-n-butylphenyl ether Asolution of parts of o-n-butylphenol in 150 parts of dry acetone wasadded dropwise over 5 hours to a stirred refluxing suspension of 80.8parts of 1.3- dibromopropane, 27.6 parts of anhydrous potassiumcarbonate and 0.5 parts of potassium iodide in I70 parts of dry acetone.

The mixture was refluxed for a further 16% hours, and filtered. Theresidue was well washed with hot acetone and the combined filtrates wereevaporated to an oil. which was dissolved in ether, washed with 10%sodium hydroxide solution and water, dried and evaporated. The residuewas distilled at 160l67/10 mm to afford 33 parts of 3-bromopropylZ-n-butylphenyl ether as a clear oil.

b. 8-[ 3-( 2n-butylphenoxy )propoxy ]-4-benzopyran-2- carboxylic acid Aporous thimble containing 11.7 parts of ethyl 8-hydroxy-4-oxo-4H-l-benzopyran-Z-carboxylate in a soxhlet apparatus wasextracted by the condensate into a stirred refluxing mixture of 14.9parts 3-bromopropyl Zn-butylphenyl ether, l3.8 parts of anhydrouspotassium carbonate. 0.5 parts of potassium iodide and 300 parts of dryacetone. The mixture was refluxed for a further 27 hours, and filtered.The filtrate was evaporated to a dark red liquid.

A mixture of 206 parts of the red liquid. 20.0 parts 35 carboxylate,1.696 parts of sodium bicarbonate and 500 parts of water was heated toeffect solution. The hot solution was filtered, allowed to cool to givea solid, which was collected and dried under vacuum over calciumchloride to furnish 8.2 parts of sodium 8-[3-(2-nbutylphenoxy)propoxy1-4-oxo-4H- l -benzopyran-2- carboxylate monohydrate.

Analysis:

Found: C, 63.5;

C H NaO..ll-I,O requires: C. 63.3;

EXAMPLE I 3 a. 7-Bromoheptyl 2-n-propylphenyl ether A mixture of 17parts of Z-propylphenyl, 97 parts of 1,7-dibromoheptane. 2 parts ofpotassium iodide and parts of anhydrous potassium carbonate was refluxedin 1000 parts of anhydrous acetone for hours. After filtration theorganic layer was concentrated and washed with 200 parts of l% sodiumhydroxide solution. The alkaline layer was washed four times with partsof ether, the combined ethereal extracts and organic layer washed withwater. dried over magnesium sulphate and evaporated to yield an amberoil which was distilled to furnish 25.3 parts of 7-bromoheptyl 2-n-propylphenyl ether. b.p. l40-l60/0.5-0.2 mm.

b. Ethyl 4-oxo-8 7-( 2-npropylphenoxy)heptyloxy ]-4H- lbenzopyran-2-carboxylate A mixture of 4.84 parts of ethyl8-hydroxy-4-oxo-4H- 1-benzopyran-Z-carboxylate, 12.5 parts of 7-bromoheptyl 2-n-propylpheny1 ether, I part of potassium iodide and 50parts of anhydrous acetone was refluxed for 76 hours. After filtrationthe organic layer was concentrated and chromatographed over silica gel.Elution with benzene/chloroform (1:1) furnished 8.9 parts of ethyl4-oxo-8-[7-(2-npropylphenoxy)heptyloxy ]-4H- 1 -benzopyran2- carboxylateas a gum.

c. 4-Oxo-8-[7-( 2-n-propy1phenoxy)heptyloxy]-4H -1-benzopyran-2-carboxylic acid A solution of 6.72 parts of sodium hydrogencarbonate in 130 parts of water was added to a refluxing solution of9.63 parts of ethyl 4-oxo'8-[7-(2-n-propylphenoxy)heptyloxy]4H- l-benzopyran-2-carboxylate in 200 parts of ethanol. More water was addedto effect a clear solution which was refluxed for 2 hours. Acidificationby concentrated hydrochloric acid, of the cooled filtrate furnished4-oxo-8-[ 7-n-propy1- phenoxy )hepty1oxy1-4H- 1 -benzopyran-2-carboxylicacid as a brown oil. The oil was triturated between water and petrol(4060) and crystallisation occurred at the interface to yield 3.4 partsof the purified acid. A solution of the acid in the minimum amount ofethanol was poured into a large volume of water and after 24 hours 2.7parts of 4-Oxo-8-[7-(2-npropylphenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylic acid hydrate were obtained as colourless needles mp 586l.

Analysis:

(1. Sodium 4-oxo-8-[ 7-( Z-n-propylphenoxy )hepty1oxy]-4H- lbenzopyran-Z-carboxylate An equivalent part of4-oxo-8-[7-(2-npropylphenoxy)hepty1oxy]-4H-l-benzopyran-2- carboxylicacid and an equivalent part of sodium hydrogen carbonate were dissolved,with heating, in 30 parts of distilled water and the correspondingsodium salt crystallised from the cooled filtrate.

Analysis:

EXAMPLE 14 4-Oxo-7-[7-(2-n-propylphenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylic acid a. Ethyl 4-oxo-7-l 7-(2-n-propy1phenoxy)heptyloxyl-4H-l benzopyran-Z-carboxylate A mixture of4.82 parts of ethyl 7-hydroxy-4-oxo-4H- l-benzopyran-2-carhoxy1ate, 12.5parts of 7- bromoheptyl (2-n-propyl)phenyl ether, 1 part of potassiumiodide and 50 parts of anhydrous potassium carbonate were refluxed in500 parts of anhydrous acetone for 64 hours. The filtrate wasconcentrated and chromatographed over silica gel to furnish l 1.3 partsof a gum which on rechromatography over silica gel afforded 5.0 parts ofethyl 4-oxo-7-[7-(2-n-propylphenoxy )heptyloxy1-4H- l-benzopyran-2-carboxy1ate which crystallised from petrol (bp. 40-60) mp.55-57.

4-Oxo-7-[7-(2-n-propy1phenoxy)hepty1oxy1-4H-1 benzopyran-2-carboxylicacid A solution of 2.15 parts of sodium hydrogen carbonate in 40 partsof water was added to a refluxing solution of 3.0 parts of ethyl4-oxo-7-[7-(2-n-propy1 phenoxy)heptyloxy]-4H-l-benzopyran-Z-carboxylatein 50 parts of ethanol. More water was added to produce a clear solutionwhich was refluxed for 2 hours. Acidification of the filtrateprecipitated the acid as a semisolid mass which was converted to a finesolid by persistent mechanical disruption of the gum cakes. The solidwas filtered off, dried and crystallised from benzene/petrol (bp. 100)to furnish 2.8 parts of 4-oxo-7-[7-(2-npropylphenoxy)heptyloxy ]-4H- 1-benzopyran-2- carboxylic acid as white microcrystals, mp. 1491 50.

Analysis:

c. Sodium 4-oxo-7-[7-(2-n-propylphenoxy)heptyloxy1-4H-1-benzopyran-2-carboxylate A solution of 0.412 parts of sodium hydrogencarbonate in 20 parts of water was added to a suspension of 2.19 partsof 4-oxo-7-[7-(2-n-propy1phenoxy)heptyloxyl-4H-1-benzopyran'Z-carboxylic acid in 30 parts ofwater and the mixture heated until a clear solution was obtained. Thefiltrate was freeze dried to furnish 2.19 parts of sodium4-oxo-7-[7-(2-n-propyl phenoxy)-heptyloxyl-41-1-1-benzopyran-2-carboxy1ate.

Analysis:

Found: C, 65.8; H, 6.6. C l-l Nao l-fio requires: C, 65.2; H, 6.5.

EXAMPLE 15 a. 6-[ 2-1-1ydroxy-3-( 2-propylphenoxy)propoxy l-4-oxo-4H-l-benzopyran-2-carboxylic acid A mixture of 19.2 parts ofpropylphenoxy) propane, 23.4 parts of ethyl 6- hydroxy-4-oxo-4H- l-benzopyran-2-carboxy1ate and 0.1 parts of benzyl trimethylammoniumhydroxide in 50 parts of dimethyl formamide was heated under reflux for3 hours. The solvent was evaporated under reduced pressure and the oilremaining dissolved in ethyl acetate. The solution was washed withdilute sodium hydroxide and water, dried over magnesium sulphate,filtered and evaporated to leave an oil. The oil was dissolved in ethylalcohol, 20.0 parts of sodium bicarbonatc was added, and the mixture wasboiled for 2 hours, during which time water was added and the ethylalcohol allowed to boil off. The aqueous solution was washed with ethylacetate and acidified with dilute hydrochloric acid to give a brownprecipitate which was collected and crystallised twice from ethylalcohol to yield 105 parts of 6-[2-hydroxy-3-(2-propylphenoxy)propoxy]-4-oxo-4H-1-benzopyran-2- carboxylic acid, meltingpoint l64-166C.

b. Sodium 6-[2-hydroxy-3-(2-propylphenoxy )propoxy]-4-oxo-4H-1-benzopyran-2-carboxylate, hemihydrate A mixture of 7.31 parts of6-[2-hydroxy-3-(2- propylphenoxy)propoxy]-4-oxo-4H- l -benzopyran-2-carboxylic acid and 1.54 parts of sodium bicarbonate in 100 parts ofwater, was heated to effect solution. The solution was filtered andfreeze dried to yield 7.5 parts of sodium 6-[2-hydroxy-3-(2-propylphenoxy)propoxy]-4-oxo-4l-l-1-benzopyran-2- carboxylate,hemihydrate.

Analysis:

Found: C, 61.6; H, 5.2. C H NaOTJM-I O requires: C. 61.5, H. 5.1%.

EXAMPLE 16 (Process (a)) 5-[2-l-lydroxy-3-(2-propylphenoxy)propoxy]-4-oxo- 4H-1-benzopyran-2-carboxylic acid a.l,2-E.poxy-3-( 2-propylphenoxy)propane To a solution of 27.2 parts of2-propylphenol and 56 parts of 1-ch1oro-2,3-epoxypropane in 30 parts ofethyl alcohol, heated under reflux, was added a solution of 13.2 partsof potassium hydroxide in 50 parts of ethyl alcohol and 6 parts of waterover minutes and the mixture obtained was heated under reflux for afurther 2 hours. The mixture was poured into 1,000 parts of water ndextracted with ethyl acetate. The organic phase was separated, washedwith water, dried over magnesium sulphate, filtered and evaporated toyield a yellow oil. The oil was distilled at the water pump to yield31.0 parts of 1,2-epoxy-3-(2-propylphenoxy)propane, boiling pointl55-l58 at 15 mm.

b. 2-Hydroxy-6-[ 2-hydroxy-3-( 2-propylphenoxy)propoxylacetophenone Asolution of 15.2 parts of 2,6-

dihydroxyacetophenone, 19.2 parts of 1,2-epoxy-3-(2-propylphenoxy)propane and 0.1 parts of benzyl trimethyl-ammoniumhydroxide in 50 parts of diemthyl formamide was heated under reflux for3 hours. The solvent was evaporated under reduced pressure and the oilremaining dissolved in ethyl acetate. The solution was washed threetimes with dilute sodium hydroxide solution and once with water, driedover magnesium sulphate, filtered and evaporated to leave an oil. Theoil was triturated with petroleum ether (bp 40-60) to yield 25.8 partsof 2-hydroxy-6-[2-hydroxy-3-(2- propylphenoxy)propoxy]acetophenone,brown solid, melting point indefinite.

as a pale A mixture of 25.8 parts of 2-hydroxy-6-[2-hydroxy-3-(2-propylphenoxy)propoxylacetophenone, 25 parts of diethyl oxalate and50 parts of dry diethyl ether was added to a stirred solution of sodiumethoxide, prepared from 6.9 parts of sodium and parts of dry ethylalcohol, and the whole was heated under reflux for 3 hours. The mixturewas poured into 1,000 parts of dilute hydrochloric acid and extractedinto ethyl acetate. The organic phase was separated and the solventremoved to leave an oil which was dissolved in 250 parts of ethylalcohol and 1 part of concentrated hydrochloric acid and heated underreflux for 15 minutes. To this solution 20.0 parts of sodium bicarbonatewere added and the mixture boiled for 2 hours, during which time waterwas added and the ethyl alcohol allowed to boil off. The resultingaqueous solution was washed with ethyl acetate and then acidified withdilute hydrochloric acid to give a pale brown precipitate. This solidwas collected by filtration and crystallised from ethyl alcohol to yield11.8 parts of 5-[2-hydroxy-3-( 2-propylphenoxy)propoxy1-4-oxo-4H-l-benzopyran 2- carboxylic acid, meltingpoint 168170c.

Analysis:

Found: C, 66.5; H. 5.8. C H O requires: C, 66.3; H, 5.6%.

d. Sodium 5-[ 2-hydroxy-3-(2-propylphenoxy)propoxy ]-4-oxo-4H-2-carboxylate dihydrate Analysis:

Found: C, 57.5; H, 5.8. C H, NaO,.2H,O requires: C, 57.9; H, .5%.

EXAMPLE l7 4-Oxo-7-( 3-[ 2-propylphenoxy[ -propoxy )-4H- 1benzopyran-2-carboxylatic acid a. 2-(3-bromopropoxy)propylbenzene Amixture of 200 parts of 2-propylbenzene, 1,500 parts of1,3-dibromo-propane, 1 10 parts of anhydrous potassium carbonate, a fewcrystals of potassium iodide and 2,000 parts of acetone was refluxed for5 days and the hot solution filtered. The residue was washed with hotacetone and the combined filtrates evaporated to give an oil which wasdissolved in chloroform.' The resulting solution was washed with 2Nsodium hydroxide Analysis:

Found: C,

56.3; H, 6.8%. C H BrO requires: C, 56.0; H, 6.6%.

b. Ethyl 4-oxo-7-( 3-[ 2-propylphenoxy]propoxy)-4H- lbenzopyran-Z-carboxylate A mixture of 58.5 parts of ethyl7-hydroxy-4-oxo-4H- l-benzopyran-2-carboxylate, 64.25 parts of 2-(3-bromopropoxy) propylbenzene, l7.25 parts of anhydrous potassiumcarbonate and 1000 parts of acetone was refluxed, with stirring, for 2%days and the hot solution filtered. The residue was washed with hotacetone and the combined filtrates evaporated to give an oil which wasdissolved in chloroform. The resulting solution was washed with 1Nsodium hydroxide solution and then dried. Evaporation of the chloroformgave an oil which yielded a solid on crystallisation from ethanol. Thesolid was chromatographed on silica gel, eluting with a l:l mixture ofethyl acetate and 40/60 light petroleum ether. Evaporation of the eluentand crystallisation of the resulting residue from ethanol gave 18.4parts of ethyl 4-oxo-7-( 3-{2-propylphenoxy1-propoxy)-4H-l-benzopyran-2-carboxylate, m.pt. 75-76.5.

Analysis:

Found: C, 70.3; H, 6.6% C l-[ ,0 requires: C, 70.2; 6.4%.

c. 4-Oxo-7-( 3-[ 2-propylphen0xy ]-propoxy)-4H- lbenzopyran-Z-carboxylic acid Analysis:

Found: C 69.2, H, 57%

C H O requires: C, 69.]; H, .8%. 60

d. Sodium4-oxo-7-(3-[2propylphenoxy]propoxy)-4H-lbenzopyran-2-carboxylate Amixture of 11.11 parts of 4-oxo-7-(3-[2- propylphcnoxy1propoxy )-4H-l-benzopyran-2- carboxylic acid and 2.4 parts of sodium bicarbonate in200 parts of water was heated to effect solution. The solution wasfiltered and freeze dried to yield 1 1.5 parts of sodium4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H- l-benzopyran-2-carboxylate.

Analysis:

Found: C,

EXAMPLE 18 (Process (a)) Ethyl 4-Oxo-7-( 3-l 2-propylphenoxy]propoxy)-4H- l benzopyran-Z-carboxylate a. 2-hydroxy-4-( 3-[2-propylphenoxy1propoxy )acetophenone A mixture of 38 parts of2,4-dihydroxyacetophenone, 64.25 parts of2-(3-bromopropoxy)propylbenzene, l7.25 parts of anhydrous potassiumcarbonate, a few crystals of potassium iodide and 500 parts of acetonewas refluxed, with stirring, for 40 hours and the hot solution filtered.The residue was washed with hot acetone and the combined filtratesevaporated to give an oil which was dissolved in chloroform. Thechloroform extract was washed with water, dried and evaporated to give aresidue which was added to 600 parts of IN sodium hydroxide solution.The solid produced was filtered, slurried in 200 parts of water and theslurry acidifed with 2N hydrochloric acid gave an oil which wasextracted into ether. Evaporation of the ether and crystallisation ofthe resulting residue from 40/60 light petroleum ether gave 38.2 partsof 2-hydroxy-4-(3-[2- propoylphenoxy]propoxy)acetophenone, m.pt. 42-43.

Analysis:

Found: C, 72.9; H, 7.4%. C H O requires: C, 72.9; H, 7.4%.

b. Ethyl 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-Z-carboxylate A solution of0.23 parts of sodium in 10 partsof ethanol was added to a solution of 0.82 parts of 2-hydroxy-4-(3-[2-propylphenoxy]propoxy)acetophenone and 1.46 parts of diethyloxalate in l5 parts of ether. The reaction mixture was stirred at roomtemperature for two hours and then poured into a mixture of 10 parts ofchloroform, 20 parts of water and 2 parts of concentrated hydrochloricacid. The organic extract was sepa rated, washed with water and dried.Evaporation of the chloroform gave an oil which was refluxed in 20 partsof ethanol containing a drop of concentrated hydro chloric acid for 30minutes. Evaporation of the solvent gave a solid which crystallised fromethanol to give 0.73 parts of ethyl 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2- carboxylate, m.pt. 73-75.

Analysis:

Found: C, 6 C H O, requires: C, 7

27 EXAMPLE 19 (Process (1 -(4-oxo-7-[ 3-2-propy1phenoxy-propoxy1-41-1-1- benzopyran-2-yl)tetrazole a. 4-oxo-7-(3-[Z-propylphenoxylpropoxy)-4H-1- benzopyran-Z-carboxamide Gaseousammonia was blubbled through a suspen-' sion of 95 parts of ethylpropylphenoxy]-propoxy)-4H-l-benzopyran-Z- carboxylate in 1140 parts ofethanol for 1 hour. The. suspension gradually changed in appearance togive a flocculent, yellow solid which was collected and washed withethanol. crystallisation of the solid from 1:1 chloroform/ethanol gave64.2 parts of 4-oxo-7-(3- [2-propylphenoxy]-propoxy)-4H-1-benzopyran-2-carboxamide, m.pt. 210213, (raised to 2122l4 by recrystallisation).

Analysis:

Found: C, 1', C H NO, requires: C, .3;

b. 4-oxo-7-(3-[ 2-propylphenoxy ]-propoxy)-4l-llbenzopyran-2-carbonitrile Analysis:

Found: C, 72.7; H, 6.1; N, 3.9%. C I-I NO requires: C, 72.7; H, 5.8; N,3.9%.

c. 5-(4-oxo-7-[ 3-2-propylphenoxy-propoxy]-4H-1-benzopyran-2-yl)tetrazole A mixture of 38.1 parts of 4-oxo-7-(3-[2-propylphenoxy]-propoxy)-4H-l-benzopyran-2- carbonitrile, 7.52 parts ofsodium azide, 6.16 parts of ammonium chloride and 5,000 parts ofdimethylformamide was stirred at 80C for hours. The reaction mixture wascooled and 2,000 parts of 2N hydrochloric acid were added to give ayellow solid which was collected. This product was dissolved in hot 3%sodium bicarbonate solution and the hot solution filtered and thencooled. The solid obtained was collected, washed with water and slurriedwith 500 parts of 2N hydrochloric acid. The resulting solid wascollected, washed with water, dried and crystallised from acetone togive 18.4 parts of 5-(4-oxo-7-[3-2-pr0pylphenoxy-propoxy1-4l-l-1-benzopyran-2-yl)-tetrazole m.pt. l9l193.

Analysis:

Found: C, 65.0; 5.0;

H, 5.7; N, 13.8%. C H N O, requires: C, 6 H, 5 4 l To 250 parts of waterwas added 16.069 parts of 5-(4-oxo-7-[3-2-propylphenoxypropoxy]-4H-lbenzopyran-Z-yl)tetrazole and 3.322 parts of sodiumbicarbonate and the mixture was heated to effect solution. The hotsolution was filtered and 50 parts of ethanol were added. On cooling, athick amorphous mass obtained which was collected and dried overphosphorus pentoxide to yield 16.8 parts of 5-(4-oxo-7-[3-2-propylphenoxy propoxy]-4l-l-1-benzopyran-2- 0 yl)tetrazole, sodium salt.

EXAMPLE 20 (Process (c)) 40xo-7-(3-[2-propylphenoxy1propoxy)-4l-llbenzopyran-Z-carboxylic acid A suspension of 1.0 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H- l -benzopyran-2- carboxamide in 10 parts ofdioxane and 10 parts of 10% "/v sulphuric acid was heated on a steam canfor 8 hours. The solid obtained on cooling was collected, washed withwater and crystallised from acetone to give 0.75 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy )-4H- 1 -benzopyran-2- carboxylic acid, m.pt.l64166.

This product was shown by spectral means to be the same as that preparedin Example 18 (c).

EXAMPLE 21 (Process (c)) 4-Oxo-7-( 3-[2-propylphenoxy]propoxy)-4H -1-benzopyran-Z-carboxylic acid A suspension of 1.0 parts of 4-Oxo-7-(3-[2-propylphenoxy]propoxy)-4l-l-1benzopyran-2- carbonitrile in 50 parts ofdioxane and 50 parts of 35% /v sulphuric acid was heated on a steam canfor 18 hours. The solid obtained on cooling was collected, washed withwater and crystallised from acetone to give 0.09 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2- carboxylic acid, m.pt. 16ll63.

This product was shown by spectral means to be the same as that preparedin Example 18(0).

EXAMPLE 22 (Process (a)) 8-Ethyl-4-oxo-7-( 3-[ 2-propylphenoxy ]propoxy)-4l-ll benzopyran-Z-carboxylic acid a. 2-Hydroxy-6-( 3-[2-propylphenoxy]propoxy)acetophenone A stirred mixture of 76 parts of2,6- dihydroxyacetophenone, 128.5 parts of 2-(3-bromopropoxy)propylbenzene, 38 parts of anhydrous potassium carbonate, afew crystals of potassium iodide and 700 parts of acetone was refluxedfor 40 hours and the hot solution filtered. The residue was washed withhot acetone and the combined filtrates evaporated to give an oil whichwas dissolved in chloroform. The resulting solution was washed with 2Nsodium hydroxide solution and water and then dried.

Evaporation of the chloroform gave a residue which crystallised fromethanol (with carbon treatment) to give 104.7 parts of2-hydroxy-6-(3-[2-propylphenoxylpropoxy)acetophenone, m.pt. 6l-64(raised to 65-66 by recrystallisation).

b. 2-Ethyl-3-(3-[2-propylphenoxy]propoxy)phenol 174.] parts of zincwool, 13.05 parts of mercuric chloride, 8.7 parts of concentratedhydrochloric acid and 216 parts of water were shaken together forminutes. The aqueous layer was decanted, the amalgamated zinc wascovered with 130.5 parts of water, 174.1 parts of concentratedhydrochloric acid, 290 parts of dioxan and 94 parts of2-hydroxy-6-(3-[2- propylphenoxy]propoxy)acetophenone and the mixturerefluxed for 16 hours. The reaction mixture was cooled, and insolublematerial removed by filtration. The organic layer was separated and theaqueous layer was extracted with chloroform. The combined organicextracts were washed with water and saturated sodium chloride solutionand dried. Evaporation of the chloroform gave 84.8 parts of 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenol, b.pt. 208-2l0/l.8 mm.

Analysis:

Found: C, 76.0; H, 8.6%. C ll- ,0 requires: C, 76.4; H, 8.3%.

c. Dimethyl 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxyfumarate Amixture of 73.9 parts of 2-ethyl-3-(3-[2- propylphenoxy1propoxy)phenol,35.0 parts of acetylene dicarboxylic acid, dimethyl ester and 4 parts ofAnalysis:

Found: C, 68.6;1-1, 7.3%. C l-I 0 requires: C, 68 4; H, 7.0%.

d. 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxyfumaric acid A solutionof 42.0 parts of dimethyl 2-ethyl-3-(3-[2-propylphenoxy1propoxy)phenoxyfumaric acid and 7.36 parts of sodiumhydroxide in 50% "/v aqueous 55 methanol was refluxed for 4 hours. Thereaction mixture was cooled, acidified with excess 2N hydrochloric acidand extracted with chloroform. Evaporation of the chloroform andtrituration of the residue with 40/60 0 ethyl8-Ethyl-4-oxo-7-(3-[2-propylphenoxy1propoxy)-4H-lbenzopyran-2-carboxylic acid Spectral Confinnation Molecular weight C HO requires 410 (Mass Spectroscopy) EXAMPLE 23 (Process (a)) 5-( 3-[2-Acetyl-3-hydroxyphenoxy]-2- hydroxypropoxy )-4-oxo-4l-l-l-benzopyran-2- carboxylic acid a. Ethyl 5-( 3-[2-acetyl-3-hydroxyphenoxy]-2- hydroxypropoxy )-4-oxo-4l-ll -benzopyran-2- carboxylate A solutionof 69.0 parts of sodium in 1000 parts of ethanol was added to a mixtureof 360.3 parts of 1,3- bis-(2-acetyl-3-hydroxyphenoxy)propan-Z-ol, 146.1parts of diethyl oxalate and 250 parts of ethanol. The reaction mixturewas refluxed for 5 hours, then poured into a stirred mixture of 700parts of chloroform, 3,000 parts of water and 285 parts of concentratedhydrochloric acid. The solid obtained was removed by filtration, thechloroform phase of the filtrate separated and the aqueous phaseextracted with chloroform. The combined chloroform extracts were washedwith water and concentrated to give a solid which was removed byfiltration. Evaporation of the chloroform from the filtrate gave aresidue which, after fractional crystallisation from ethanol, gave 36.0parts of slightly impure 5-( 3-[Z-acetyl-3-hydroxyphenoxy1-2-hydroxypropoxy )-4-oxo-4H- l -benzopyran-2- carboxylate, m.pt. l45l48.

b. Sodium 5-( 3-[2-acetyl-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2- carboxylate 32.0 parts of ethyl5-(3-[2-acetyl-3- light petroleum ether gave an oily solid. This solidwas hydroxyphenoxy] g hydmxypropoxy 4 4 dissolved in hot chloroform andaddition of 40/60 light petroleum ether to the solution gave 33.8 partsof 2- ethyl-3-( 3- 2-propylphenoxy propoxy )phenoxyfumaric acid, m.pt.104l05.

Spectral Confirmation Molecular weight 428 (Mass Spectroscopy) C H O,requires 428 benzopyran-Z-carboxylate were refluxed with a solution of6.08 parts of sodium bicarbonate in 200 parts of water for 18 hours. Thesolution was filtered hot and cooled. The solid obtained was collectedby filtration and crystallised from water containing a small quantity ofethanol to give 9.2 parts of sodium 5-(3-[2-acetyl-3- hydroxyphenoxyl-2-hydroxypropoxy)-4-oxo-4H- l benzopyran-2-carboxylate, m.pt. l78-l80.

Analysis:

Found: C, 55.10; H, 4.34%. C H NaO H requires: C, 55.50; H, 4.21%.

EXAMPLE 24 (Process (a)) Ethyl -(3-[4-ox0-4H-1-benzopyran-5-yloxy]-2-hydroxypropoxy )-4-oxo-4H 1 -benzopyran-2- carboxylate A solution of7.36 parts of sodium in l 1 1 parts of ethanol was added to a suspensionof 14.4 parts of 1,3- bis(2-acetyl-3-hydroxyphenoxy)propan-2-ol in 23.68parts of ethyl formate and 63.3 parts of ethanol and the reactionmixture stirred at room temperature for 3 days. 46.8 parts of diethyloxalate were then added and the reaction mixture stirred for a further16 hours. The suspension was poured into a stirred mixture of 370 partsof chloroform and 250 parts of 2N hydrochloric acid and the organicextract separated, washed with water and dried.

Evaporation of the chloroform gave an oil which was refluxed for 1 hourin 316 parts of ethanol containing 4 parts of concentrated hydrochloricacid. A solid was obtained by cooling the solution. On fractionalcrystallisation (twice) of this product from ethanol, a yellow solid wasobtained by evaporation of the mother liquors of the secondcrystallisation. Chromotagraphy of this solid on silica gel, elutingwith 1:1 toluene/acetic acid, gave a solid which crystallised fromethanol to give 0.138 parts of ethyl 5-(3-[4-oxo-4H-l-benzopyran-5-yloxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2- carboxylate, m.pt.l55-l59.

Spectral Confirmation The nmr and mass spectral data were in agreementwith the indicated structure.

Molecular weight 452 (Mass spectroscopy) CgqHioOg requries 452 EXAMPLE25 (Process (e) and (f)) Ethyl 5-(3-[4-oxo-4H-1-benzopyran-5-yl0xy]-2-hydroxypropoxy)-4'oxo-4H-1-benzopyran-2- carboxylate a. Ethyl 5-(3-[2-3-dimethylaminoacryloyl 3- hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate b. Ethyl5-(3-[4-0xo-4H-1-benzopyran-5-yloxy]-2- hydroxypropoxy)-4-oxo-4H- l-benzopyran-2- carboxylate 0.200 parts of ethyl 5-(3-[2- 3-dimethylaminoacryloyl -3-hydroxyphenoxy]-2- hydroxypropoxy )-4-oxo-4H- l-benzopyran-2- carboxylate were refluxed for 16 hours in 15.8 parts ofethanol containing 1 part of concentrated hydrochloric acid. Thesolution was poured into a stirred mixture of 10 parts of water and 73parts of chloroform and the organic extract separated, and washed with5% sodium bicarbonate solution and water. Evaporation of the chloroformgave a residue which was chromatographed on silica gel, eluting with 1:1chloroform/ethyl acetate. The product obtained from chromatography wascrystallised from ethanol to give 0.027 parts of ethyl 5-(3-[4-oxo-4H-1-benzopyran-5-yloxy]-2- hydroxypropoxy)-4-oxo-4H-1-benzopyran-2- carboxylate, m.pt. l54158.

Spectral Confirmation The n.m.r. and mass spectral data were inagreement with the indicated structure.

molecular weight C H O, requires EXAMPLE A The procedure set out belowis used to assess the effectiveness of a compound in antagonizing SRS-A.The test makes use of the agonist (contractile) effect of SRS-A onisolated guinea-pig ileum.

A satisfactory preparation of SRS-A can be obtained from egg albumensensitised guinea-pigs. Three weeks after sensitisation, the lungs fromsuch guinea-pigs are removed, perfused free of blood, and chopped.Samples of washed, chopped lung are then challenged with egg albumen(antigen) solution. The supernatants collected 15 minutes after additionof antigen contain his tamine and SRS-A and can be used, in the presenceof an antihistamine, to induce effects due to SRS-A.

An isolated section of the terminal portion of a guinea-pig ileum issuspended in Tyrode solution, which contains atropine sulphate lO- M(700 ,ug/litre) and mepyramine maleate IO-M (400 rig/litre). Atropinesulphate is included to reduce the spontaneous activity of the ileumpreparation and to exclude the effects of possible cholinergic agents.Mepyramine maleate is included to exclude the effects of histamine. Thecomposition of the Tyrode solution in g/1 distilled water is NaCl 8.0,KC10.2, CaCl 0.2, MgCl 0.1, NaHCO 1.0, Na1-l PO 2H O 0.05 and dextrose1.0. A 2ml organ bath is preferred for economy of SRS-A, the tension onthe tissue should be about 600 mg and the bathing temperature 37C.

A dose of unpurified SRS-A is selected which produces similar repetitivesubmiximal contractions of the ileum. Eact contraction is recorded forseconds when the tissue is washed to allow relaxation. Five minutes isallowed between doses of SRS-A.

The compound under test is added to the organ bath 30 seconds before adose of SRS-A. A range of concentrations of the compound is chosen togive a log concentration/inhibitory response graph. From this graph, theconcentration of compound which would inhibit the ileum contraction toSRS-A by 50% (lC is determined.

We claim:

1. A compound of the formula wherein X is a straight chain alkylenegroup containing from 3 to 7 carbon atoms and is unsubstituted or issubstituted by one hydroxy group, B is a carboxy group and R R and R maybe the same or different and are hydrogen, hydroxy, methoxy, benzyloxy,acetyl, acetylamino, allyl or propyl and R is hydrogen, allyl or propyl,

and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein R is H, X is pentyl, R is4-acetyl, R is 3OH and R is H and the OXOgroup is attached to thechromone group in the 7-position.

3. A compound according to claim 1 wherein R is 8-allyl, X is pentyl, Ris 4-acetyl, R is 3OH, R is 2- allyl and the OXOgroup is attached to thechrmone group in the 7-position.

4. A compound according to claim 1 wherein R is 8-allyl, X is pentyl, Ris 4-acetyl, R is H, R is H and the OXOgroup is attached to the chromonegroup in the 7 position.

5. A compound according to claim 1 wherein R is 8-allyl, X is pentyl, Ris 2-acetyl, R is 3OH, R is H and the OXOgroup is attached to thechromone group in the 7-position.

6. A compound according to claim 1 wherein R is 8-allyl, X is pentyl, Ris 4-acetylamino, R is H, R is H and the OXOgroup is attached to thechromone group in the 7-position.

7. A compound according to claim 1 wherein R is H, X is pentyl, R is4-acetyl, R is H, R is H and the OXOgroup is attached to the chromonegroup in the 7-position.

8. A compound according to claim I wherein R is H, X is pentyl, R is 3CHO, R is H, R is H and the OXOgroup is attached to the chromone group inthe 7-position.

9. A compound according to claim 1 wherein R is H, X is pentyl, R is3-benzyloxy, R is H, R is H and the OXOgroup is attached to the chromonegroup in the 7-position.

10. A compound according to claim 1 wherein R is H, X is pentyl, R is2-acetyl, R is 3OH, R is 4-allyl and the OXOgroup is attached to thechromone group in the 7-position.

11. A compound according to claim 1 wherein R is 8-allyl, X is 2OHpropyl, R is 4-acetyl, R is 2-allyl, R

is 3-OH and the OXOgroup is attached to the chromone group in the7-position.

12. A compound according to claim 1 wherein R is H, X is 2OH propyl, Ris 4-acetyl, R is H, R is 3-OH and the OXOgroup is attached to thechromone group in the 7-position.

13. A compound according to claim 1 wherein R is 8-allyl, X is 2OHpropyl, R is 4-acetyl, R is H, R is 3-OH and the OXOgroup is attached tothe chromone group in the 7-position.

14. A compound according to claim 1 wherein R is H, X is 2OH propyl, Ris 4-acetyl, R is 2-allyl, R is 3-OH and the OXOgroup is attached to thechromone group in the 7-position.

15. A compound according to claim I wherein R is S-propyl, X is 2OHpropyl, R" is 4-acetyl, R is 2- propyl, R is 3-0H and the OXOgroup isattached to the chromone group in the 7-position.

16. A compound according to claim 1 wherein R is 8-propyl, X is 2OHpropyl, R is H, R is 2-propyl R is H and the OXOgroup is attached to thechromone group in the 7-position.

17. A compound according to claim 1 wherein R is H, X is 2OH propyl, Ris 2-propyl, R is H, R is H and the OXOgroup is attached to the chromonegroup in the 7-position.

l8. A compound according to claim 1 wherein R is H, X is 2OH propyl, Ris 2-allyl, R is H, R is H and the OXOgroup is attached to the chromonegroup in the 7-position.

19. A compound according to claim 1 wherein R is H, X is 2OH propyl, Ris 4-acetyl, R is 3OH, R is 2-propyl and the OXOgroup is attached to thechromone group in the 7-position.

20. A compound according to claim 1 wherein R is 6-propyl, X is 2OHpropyl, R is 2-propyl, R is H, R is H and the OXOgroup is attached tothe chromone group in the 7-position.

21. A compound according to claim 1 wherein R is 8-propyl, X is 2OHpropyl, R is 4-acetyl, R is 3OH, R is 2-propyl and the OXOgroup isattached to the chromone group in the 7-position and thepharmaceutically acceptable salt is the tris (hydroxymethyl)methylaminesalt.

22. A compound according to claim 1 wherein R is 8-propyl, X is propyl,R is 4-acetyl, R is 3-OH, R is 2-propyl and the OXOgroup is attached tothe chromone group in the 7-position.

23. A compound according to claim 1 wherein R is S-propyl, X is propyl,R is 2-propyl, R is H, R is H and the OXOgroup is attached to thechromone group in the 7-position.

24. A compound according to claim 1 wherein R is 6-propyl, X is propyl,R is 2-propyl, R is H, R is H and the OXOgroup is attached to thechromone group in the 7-position.

25. A compound according to claim 1 wherein R is H, X is 2OH propyl, Ris H, R is S-OH, R is 2- acetyl and the OXOgroup is attached to thechromone group in the 5-position.

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereinR4 is H, X is pentyl, R3 is 4-acetyl, R2 is 3-OH and R1 is H and the-OXO-group is attached to the chromone group in the 7-position.
 3. Acompound according to claim 1 wherein R4 is 8-allyl, X is pentyl, R3 is4-acetyl, R2 is 3-OH, R1 is 2-allyl and the -OXO-group is attached tothe chromone group in the 7-position.
 4. A compound according to claim 1wherein R4 is 8-allyl, X is pentyl, R3 is 4-acetyl, R2 is H, R1 is H andthe -OXO-group is attached to the chromone group in the 7-position.
 5. Acompound according to claim 1 wherein R4 is 8-allyl, X is pentyl, R3 is2-acetyl, R2 is 3-OH, R1 is H and the -OXO-group is attached to thechromone group in the 7-position.
 6. A compound according to claim 1wherein R4 is 8-allyl, X is pentyl, R3 is 4-acetylamino, R2 is H, R1 isH and the -OXO-group is attached to the chromone group in the7-position.
 7. A compound according to claim 1 wherein R4 is H, X ispentyl, R3 is 4-acetyl, R2 is H, R1 is H and the -OXO-group is attachedto the chromone group in the 7-position.
 8. A compound according toclaim 1 wherein R4 is H, X is pentyl, R3 is 3-CH3O, R2 is H, R1 is H andthe -OXO-group is attached to the chromone group in the 7-position.
 9. Acompound according to claim 1 wherein R4 is H, X is pentyl, R3 is3-benzyloxy, R2 is H, R1 is H and the -OXO-group is attached to thechromone group in the 7-position.
 10. A compound according to claim 1wherein R4 is H, X is pentyl, R3 is 2-acetyl, R2 is 3-OH, R1 is 4-allyland the -OXO-group is attached to the chromone group in the 7-position.11. A compound according to claim 1 wherein R4 is 8-allyl, X is 2-OHpropyl, R3 is 4-acetyl, R2 is 2-allyl, R1 is 3-OH and the -OXO-group isattached to the chromone group in the 7-position.
 12. A compoundaccording to claim 1 wherein R4 is H, X is 2-OH propyl, R3 is 4-acetyl,R2 is H, R1 is 3-OH and the -OXO-group is attached to the chromone groupin the 7-position.
 13. A compound according to claim 1 wherein R4 is8-allyl, X is 2-OH propyl, R3 is 4-acetyl, R2 is H, R1 is 3-OH and the-OXO-group is attached to the chromone group in the 7-position.
 14. Acompound according to claim 1 wherein R4 is H, X is 2-OH propyl, R3 is4-acetyl, R2 is 2-allyl, R1 is 3-OH and the -OXO-group is attached tothe chromone group in the 7-position.
 15. A compound according to claim1 wherein R4 is 8-propyl, X is 2-OH propyl, R3 is 4-acetyl, R2 is2-propyl, R1 is 3-OH and the -OXO-group is attached to the chromonegroup in the 7-position.
 16. A compound according to claim 1 wherein R4is 8-propyl, X is 2-OH propyl, R3 is H, R2 is 2-propyl R1 is H and the-OXO-group is attached to the chromone group in the 7-position.
 17. Acompound according to claim 1 wherein R4 is H, X is 2-OH propyl, R3 is2-propyl, R2 is H, R1 is H and the -OXO-group is attached to thechromone group in the 7-position.
 18. A compound according to claim 1wherein R4 is H, X is 2-OH propyl, R3 is 2-allyl, R2 is H, R1 is H andthe -OXO-group is attached to the chromone group in the 7-position. 19.A compound according to claim 1 wherein R4 is H, X is 2-OH propyl, R3 is4-acetyl, R2 is 3-OH, R1 is 2-propyl and the -OXO-group is attached tothe chromone group in the 7-position.
 20. A compound according to claim1 wherein R4 is 6-propyl, X is 2-OH propyl, R3 is 2-propyl, R2 is H, R1is H and the -OXO-group is attached to the chromone group in the7-position.
 21. A compound according to claim 1 wherein R4 is 8-propyl,X is 2-OH propyl, R3 is 4-acetyl, R2 is 3-OH, R1 is 2-propyl and the-OXO-group is attached to the chromone group in the 7-position and thepharmaceutically acceptable salt is the tris (hydroxymethyl)methylaminesalt.
 22. A compound according to claim 1 wherein R4 is 8-propyl, X ispropyl, R3 is 4-acetyl, R2 is 3-OH, R1 is 2-propyl and the -OXO-group isattached to the chromone group in the 7-position.
 23. A compoundaccording to claim 1 wherein R4 is 8-propyl, X is propyl, R3 is2-propyl, R2 is H, R1 is H and the -OXO-group is attached to thechromone group in the 7-position.
 24. A compound according to claim 1wherein R4 is 6-propyl, X is propyl, R3 is 2-propyl, R2 is H, R1 is Hand the -OXO-group is attached to the chromone group in the 7-position.25. A compound according to claim 1 wherein R4 is H, X is 2-OH propyl,R3 is H, R2 is 3-OH, R1 is 2-acetyl and the -OXO-group is attached tothe chromone group in the 5-position.